Baruch S. Blumberg

Biographical

I was born in 1925, in New York City, the second of three children of Meyer and Ida Blumberg. My grandparents came to the United States from Europe at the end of the 19th century. They were members of an immigrant group who had enormous confidence in the possibilities of their adopted country. I received my elementary education at the Yeshiva of Flatbush, a Hebrew parochial school, and, at an early age, in addition to a rigorous secular education, learned the Hebrew Testament in the original language. We spent many hours on the rabbinic commentaries on the Bible and were immersed in the existential reasoning of the Talmud at an age when we could hardly have realized its impact.

After attending Far Rockaway High School I joined the U.S. Navy in 1943 and finished college under military auspices. I was commissioned as a Deck Officer, served on landing ships, and was the commanding officer of one of these when I left active duty in 1946. My interest in the sea remained. In later years I made several trips as a merchant seaman, held a ticket as a Ships Surgeon, and, while in medical school, occasionally served as a semiprofessional hand on sailing ships. Sea experience placed a great emphasis on detailed problem solving, on extensive planning before action, and on the arrangement of alternate methods to effect an end. These techniques have application in certain kinds of research, particularly in the execution of field studies.

My undergraduate degree in Physics was taken at Union College in upstate New York, and in 1946 I began graduate work in mathematics at Columbia University. My father, who was a lawyer, suggested that I should go to medical school, and I entered The College of Physicians and Surgeons of Columbia University in 1947. I enjoyed my four years at the College immensely. Robert Loeb was the chairman of the Department of Medicine and exerted a marked influence on the entire college. There was a strong emphasis on basic science and research in the first two years (we hardly saw a patient till our third year), and we learned practical applications only in our last years.

Between my third and fourth years, Harold Brown, our professor of parasitology, arranged for me to spend several months at Moengo, an isolated mining town, accessible only by river, in the swamp and high bush country of northern Surinam. While there we delivered babies, performed clinical services, and undertook several public health surveys, including the first malaria survey done in that region. Different people had been imported into the country to serve as laborers in the sugar plantations, and they, along with the indigenous American Indians, provided a richly heterogeneous population. Hindus from India, Javanese, Africans (including the Djukas, descendants of rebelled slaves who resided in autonomous kingdoms in the interior), Chinese, and a smattering of Jews descended from 17th century migrants to the country from Brazil, lived side by side. Their responses to the many infectious agents in the environment were very different. We were particularly impressed with the enormous variation in the response to infection with Wuchereria bancroftia (the filariad which causes elephantiasis), and my first published research paper was on this topic. This experience was recalled in later years when I became interested in the study of inherited variation in susceptibility to disease. Nature operates in a bold and dramatic manner in the tropics. Biological effects are profound and tragic. The manifestations of important variables may often be readily seen and measured, and the rewards to health in terms of prevention or treatment of disease can be great. As a consequence, much of our field work has been done in tropical countries.

I was an intern and assistant resident on the First (Columbia) Division at Bellevue Hospital in lower New York from 1951 to 1953. It is difficult to explain the fascination of Bellevue. In the days before widespread health insurance, many of the city’s poor were hospitalized at Bellevue, including many formerly middle class people impoverished by the expenses of chronic illness. The wards were crowded, often with beds in the halls. Scenes on the wards were sometimes reminiscent of Hogarth’s woodcuts of the public institutions of 18th century London. Despite this, morale was high. We took great pride that the hospital was never closed; any sick person whose illness warranted hospitalization was admitted, even though all the regular bed spaces were filled. A high scientific and academic standard was maintained. Our director, Dickinson W. Richards, and his colleague, André F. Cournand, received the Nobel Prize for their work on cardio-pulmonary physiology. Anyone who has been immersed in the world of a busy city hospital, a world of wretched lives, of hope destroyed by devastating illness, cannot easily forget that an objective of big-medical research is, in the end, the prevention and cure of disease.

I spent the following two years as a Clinical Fellow in Medicine at Columbia Presbyterian Medical Center working in the Arthritis Division under Dr. Charles A. Ragan. I also did experimental work on the physical biochemistry of hyaluronic acid with Dr. Karl Meyer. From 1955 to 1957, I was a graduate student at the Department of Biochemistry at Oxford University, England, and a member of Balliol College. I did my Ph.D. thesis with Alexander G. Ogston on the physical and biochemical characteristics of hyaluronic acid. Professor Ogston’s remarkable combination of theory and experiment guided the scientific activity in his laboratory. He has served as a model to me on how to train students; I hope I have measured up to his standard. Sir Hans Krebs was the chairman of the Department of Biochemistry. I have profited by conversations with him, particularly when (in 1972) I was a visiting fellow at Trinity College and we had opportunities to discuss our mutual interests in the history of science.

Oxford science at that time was influenced by the 19th and 20th century British and European naturalists, scientists and explorers who went to the world of nature – often to distant parts of it – to make the observations which generated their hypotheses. Anthony C. Allison was then working in the Department of Biochemistry and introduced me to the concept of polymorphism, a term introduced by the lepidopterist E. B. Ford of the Department of Zoology. In 1957 I took my first West African trip (to Nigeria) and was introduced to the special excitement of that part of the world. I found the Nigerians warmhearted and friendly with a spontaneous approach to life. We collected blood specimens from several populations (including the nomadic pastoral Fulani and their domestic animals) and studied inherited polymorphisms of the serum proteins of milk and of hemoglobin. This approach was continued in many subsequent field trips, and it eventually led to the discovery of several new polymorphisms and, in due course, the hepatitis B virus.

I worked at the National Institutes of Health from 1957 until 1964. This was during a period of rapid growth for the NIH, and I continued to develop my research on polymorphisms and their relation to disease. This led to the formation of the Section on Geographic Medicine and Genetics, which was eventually assigned to an epidemiology branch directed by Thomas Dublin, from whom I learned the methods of epidemiology. The NIH was a very exciting place, with stimulating colleagues including J. Edward Rall, Jacob Robbins, J. Carl Robinson, Kenneth Warren, Seymour Geisser, and many others. The most important connection I made, however, was with W. Thomas London (who later came to The Institute for Cancer Research), who has become a colleague, collaborator, and good friend with whom I have worked closely for fifteen years. Tom was an essential contributor to the work on Australia antigen and hepatitis B, and without him it could not have been done.

I came to The Institute for Cancer Research in 1964 to start a program in clinical research. The Institute was, and is, a remarkable research organization. Our director, Timothy R. Talbot, Jr., has a deep respect for basic research and a commitment to the independence of the investigators. Above all, people are considered an end in themselves, and the misuse of staff to serve some abstract goal is not tolerated. Jack Schultz was a leading intellectual force in the Institute, and his foresighted, humane view of science, his honesty and his good sense influenced the activities of all of us. Another important characteristic is the dedication and intelligence of our administrative and maintenance staffs, which contributes to the strong sense of community which pervades our Institute.

Over the course of the next few years we built up a group of investigators from various disciplines and from many countries (Finland, France, Italy, Poland, Venezuela, England, India, Korea, China, Thailand, Singapore) who, taken together, did the work on Australia antigen. Alton I. Sutnick (now Dean of the Medical College of Pennsylvania) was responsible for much of the clinical work at Jeanes Hospital. Some of the early workers included Irving Millman, Betty Jane Gerstley, Liisa Prehn, Alberto Vierucci, Scott Mazzur, Barbara Werner, Cyril Levene, Veronica Coyne, Anna O’Connell, Edward Lustbader, and others. There were many field trips during this period to the Philippines, India, Japan, Canada, Scandinavia, Australia, and Africa. It has been an exciting and pleasant experience surrounded by stimulating and friendly colleagues.

At present, we are conducting field work in Senegal and Mali, West Africa, in collaboration with Professor Payet of Paris, formerly the Dean of the Medical School of Dakar, with Professor Sankalé, his successor in Dakar, and a group of other French and Sengalese colleagues, including Drs. Larouzé and Saimot.

I am Professor of Medicine at the University of Pennsylvania and attend ward rounds with house staff and medical students. I am also a Professor of Anthropology and have taught Medical Anthropology for eight years. I have learned a great deal from my students.

My non-scientific interests are primarily in the out-of-doors. I have been a middle distance runner (very non-competitive) for many years and also play squash. We canoe on the many nearby lakes and rivers of Pennsylvania and New Jersey. I enjoy mountain walking and have hiked in many parts of the world on field trips. With several friends we own a farm in western Maryland which supplies beef for the local market. Shoveling manure for a day is an excellent counterbalance to intellectual work.

My wife, Jean, is an artist who has recently become interested in print making. We have four children of whom I am very proud: Anne, George, Jane, and Noah. They are all individualists, which makes for a turbulent and noisy household, still we miss the two oldest who are now away at college. We live in the center of old Philadelphia, a few blocks from Independence Hall. The city has appreciated its recognition by the Nobel Award in our Bicentennial Year.

This autobiography/biography was written
at the time of the award and later published in the book series Les
Prix Nobel/Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted
by the Laureate.

Addendum, August 2006

The editors of the Nobelprize.org website of the Nobel Foundation have asked me to provide a supplement to the autobiography that I wrote in 1976 and to recount the events that happened after the award. Much of what I will have to say relates to the scientific developments since the last essay. These are described in greater detail in a scientific memoir first published in 2002 (Blumberg, B. S., Hepatitis B. The Hunt for a Killer Virus, Princeton University Press, 2002, 2004).

The Nobel award led to profound changes in my professional and personal life. There was some excitement in Philadelphia – a Nobel Prize had not been awarded to one of our citizens since 1972 and only two since then – but that soon quieted down. The most important effects had to do with our research. By 1976 there was general agreement on the identification of the hepatitis B virus (HBV) and the work on the molecular biology had started, much of it at the Fox Chase Cancer Center. The immunodiffusion test for detecting the virus was widely used to prevent the use of blood donations from carriers of HBV. This program became more effective with the introduction of the specific HBV radioimmunoassay we had invented, and improved further when more sensitive and convenient tests developed by other laboratories became available. Within a few years, post transfusion hepatitis due to HBV had been essentially eliminated in the United States and many other countries. This however did not completely solve the problem of post transfusion hepatitis and it became apparent that there was an additional blood borne virus that also caused post-transfusion hepatitis. This was referred to temporarily as the non-A, non-B virus until the hepatitis C virus was discovered in the mid-1980s and there was a second dramatic drop in post transfusion hepatitis. The tests for HBV and HCV are now used widely and post transfusion hepatitis is well controlled in most countries with good medical and public health facilities.

A major focus of our research at the time the prize was awarded was the etiological relation between HBV and primary cancer of the liver (hepatocellular carcinoma, HCC). As early as 1969 Bruce Smith and I had postulated that HBV was a cause of primary cancer of the liver. By the mid-1970s we were fully engaged in testing this model in Senegal in collaboration with Senegalese and French colleagues and other investigations were in progress in several laboratories in Asia and elsewhere (see below). A very important contribution was a prospective epidemiological study in Taiwan by Beasley and his colleagues. They determined that carriers of HBV had more than a 200 times higher risk of developing HCC than controls who were not carriers.

In the following sections I will describe what I believe to be the high points of the 30 years since the Nobel award.

ChinaThese findings precipitated what was probably the most important field trip of my life, a life that has included many field trips. In the mid-1970s I read an abstract of a paper presented at an international cancer congress held in Florence, Italy describing the epidemiology of cancer of the liver in China. The prevalences cited were extremely high; HCC was one of the most common cancers in the most populous country on the globe. Our earliest studies showed a high frequency of Australia antigen, the surface antigen of HBV, in Asians and Pacific Islanders. This combined with our invention of the vaccine, whose development by drug companies was just starting, made it clear that it was important to visit China to tell scientists and public health officials about HBV research and its practical applications, and to learn more about the situation in China. This would be of help, not only to the Chinese populations, but to those at risk of developing chronic liver disease and HCC worldwide.

Recall that this was at a time when the United States and the Peoples Republic of China did not have diplomatic relations. Contacts between the two countries had been few and sporadic. The US Ping Pong team had, unexpectedly, been invited to visit their colleagues in China from April 11th to 17th 1971. President and Mrs. Nixon had visited China February 21-27, 1974 but the US and China did not exchange Ambassadors and have regular diplomatic relations until January 1, 1979. In the interim, there was a Liaison Office; George H.W. Bush, later the President of the US, was the United States liaison in the mid-1970s. During this period there were occasional visits by scientific and other groups from the United States and elsewhere.

Beginning in the early 1970s we had contacted the Committee for Friendly Cooperation with China, a US Government related organization formed to facilitate scientific and cultural interactions between China and the United States. Through them I had been in contact with the Chinese Medical Association; letters were exchanged, but there was no further progress. Soon after the award of the Nobel Prize in 1976, I received an invitation from the Association to visit China as their guest for several weeks. I believe that the invitation was a consequence of the Prize and, in the view of my Chinese hosts, the status that it conferred. This was an early example of the advantages that accompanied the prize.

I flew first to Japan and met with my colleague Professor K. Nishioka. He told me that, in 1974, a deputation from China had come to Tokyo to learn the methods for detection of HBV. Later, while in China, I learned that Premier Chou En-lai had favored the introduction of these techniques against a prevailing political opposition that regarded any foreign technology as suspect. On 10.07.77 I flew to Peking (now Beijing ) from Tokyo and was greeted by representatives of the Chinese Medical Association and officials of the Communist party. The CMA was a non-governmental organization but there were always Party officials among those who formally greeted me at the several cities I visited. Thereupon followed a hectic visit traveling by car, train, crowded airplanes, and foot. I spoke to several thousand scientists at well attended lectures many lasting for three or more hours. I told them of the recent advances in HBV research, described the procedures in place for testing donor blood, and gave them a copy of our HBV vaccine patent and other information on the production and use of the vaccine. (At that time the Chinese did not respect patent protection.) I put them in contact with Merck & Company, Inc. whom we had licensed to produce the HBV vaccine, and they eventually arranged an exchange of technical information that allowed the Chinese to produce vaccine in-country. For years afterwards on my return visits to China and in speaking with the many Chinese scientists who came to study and work in the United States and Britain (where I lived between 1989 and 1994) they told me that they had heard me speak during the 1977 visit and that it had influenced their work. I believe, though of course it is difficult to be certain, that my visit accelerated the research on HBV and its application to testing and, in particular, in moving forward the vaccination program. If so, then the visit could have been responsible for saving many lives.

My strongest memories of the trip were not the intense scientific discussions I had with the many scientists and others I met, but rather the time that I spent walking or running by myself through the early morning streets of Peking (Beijing), Shanghai, Quilan, Canton (as it was then), and in rural locations. During the day and in the evening I was accompanied by a political guide and an eminent Chinese scientist, Dr. Sun Tsung-tang – himself a pioneer in hepatitis research – but no one seemed to mind when I arose early in the morning and ran for miles through the places we were visiting. A running, middle aged, bald American was not a common site in Tiananmen Square, or the other venues for my runs, but it allowed me to see the everyday life of the China of that time. The country was emerging from the great Cultural Revolution, and the “Gang of Four”, including Mao’s wife had only recently been deposed. There were few automobiles, the streets of Beijing were dominated by masses of bicycles, and government control was still very obvious. It was far different from contemporary China that I saw on visits more than 25 years later, a country that had vigorously entered the world’s industrial and information revolution.

The following year, 1978, I visited Taiwan. Research on HBV was already well advanced and testing of donor blood for HBV carriers was nearly universal. They were preparing for vaccination programs even though the vaccine was not yet tested or approved. I visited the blood bank and was impressed with the organization of their testing facilities and the quality of the data management for the donor blood testing. I asked what they did with the blood donor units that were positive for HBV; they told me that they were stored for a period and then disposed of. I suggested that they acquire deep freeze units, store the separated plasma and that, in time, when the production of vaccine began, they could be used as a source of the surface antigen that was used to make the vaccine. (The vaccine we had invented was made from the surface antigen particles of HBV found in great quantities in the blood of HBV carriers.) When I returned to Taiwan in June of 1986 I was invited to visit the Taipei Blood Donor center. My host told me that they had a new building since my last visit and that there were other new blood bank building elsewhere on the island. They had followed my suggestion, stored the sera of the carriers and sold it for the manufacture of vaccine! I was surprised to find my picture on the wall commemorating my earlier visit. As the years go by, I seem to be asked for advice on a wide variety of subjects but this was one of the rare times that it was actually followed.

Hepatocellular Carcinoma and West Africa As already noted, a major focus of our research in the mid-1970s had been on the relation of HBV to primary cancer of the liver. My laboratory was at the Fox Chase Cancer Center, an institution dedicated to the treatment, cure and prevention of cancer. When I started the research on blood polymorphisms, the Australia antigen, and later the hepatitis B virus, there was little evidence that it had any relation to cancer. Our Center emphasized basic research on the nature of the normal cell and on genetics with the expectation that this research, in turn, could lead to a better understanding of the cancer process. We were given wide latitude in our choice of research topics and they did not have to pass the test of relevance to cancer. However, in time, the sponsoring agencies for the research, primarily the National Cancer Institute of the National Institutes of Health, did want some reassurance that, eventually, the research would impact on the group of diseases that it was empowered to fund.

Primary cancer of the liver (HCC) is not common in the United States. Where should we do our research? We needed to study the problem in the field and in a location where there was both a high prevalence of HBV and of HCC, along with a felt concern in the population about the diseases that would stimulate interest and collaboration.

In 1972, while I was the Visiting Fellow in Oxford, Dr. Bernard Larouze, at that time at Hopital Claude Bernard, in Paris in the Department of Professor Maurice Payet came to visit me in my office at the Laboratory of Genetics (then headed by Professor Sir Walter Bodmer) in the Department of Biochemistry. He asked if I could collaborate with him, his Professor, and Senegalese scientists at the University of Dakar to work on hepatitis and HCC. We agreed and for the next twenty years our research group had an ongoing program in Senegal. I visited Senegal and Mali on several occasions and once again enjoyed the ambience of West African life. Our work contributed to the understanding of the etiological association of HBV with HCC and we helped to establish some of the criterion for a vaccination program. In particular, in a multiple year study in Thies, a provincial center to the east of Dakar, we showed that children were often infected by their HBV carrier mothers, probably at the time of birth or soon afterwards, but that the carrier state was not manifest until several months after birth. This provided an interval when vaccination could be effective. Interestingly, in Asia, the carrier state was detected much sooner after delivery than in Senegal, but even there the vaccine proved to be effective if administered at birth or soon thereafter. This suggested that the vaccine might protect even after infection but before the carrier state was established.

It was nothing short of providential that the vaccine was effective in newborns because, in time, when the vaccine became available in commercial quantities (more about this later) extensive vaccination programs could be launched that protected even the children of carrier mothers from the development later in life of chronic liver disease and primary cancer of the liver. This was one of the most gratifying consequences of all our research. At a meeting in Barcelona (05.07.90), Dr. P. Pasquini of the Instituto Superiore di Sanita in Rome thanked me for saving some 9000 lives per year in Italy and, if I recall correctly, specifically extended the thanks of tens of thousands of Italian women who could now have children without fear of transmitting HBV to them.

My colleague, Tom London, had the major role in the Senegal program and continued it for many years when I stepped down as the Principal Investigator of our group at FCCC in 1989. He and his colleagues undertook a large epidemiological study in Senegal and, at the same time, in coastal China. They made fundamental contributions to the understanding of the dynamics of viral carcinogenesis that will inform the prevention program, treatment, and the search for other viral-caused cancers.

Hepatitis B vaccineWe invented (and the Fox Chase Cancer Center had patented) the vaccine for HBV in 1969, but it would take some time before we could interest a pharmaceutical company to help develop and produce it. Vaccines are not an attractive product for pharmaceutical companies in that they are often used once or only a few times and they ordinarily do not generate as much income as a medication for a chronic disease that must be used for many years. Also, the medical research community was, in the early 1970s, far from convinced that we had identified the virus and much less that we had produced a vaccine using a non-conventional method. However by the mid-1970s we reckoned that there was sufficient evidence for a concerted campaign to find a company that we could license. The National Institutes of Health, who had financed much of the research, retained the domestic rights to the patent but granted FCCC the foreign rights. Irving Millman, the co-inventor, and I sought an appropriate manufacturer. On 08.07.76, FCCC signed an agreement with Merck & Company, Inc., whose vaccine facilities were located near Philadelphia, to produce the vaccine using the novel method we had designed. The vaccine was made from small HBV surface antigen particles, made in the liver cells of the human host guided by the surface antigen gene introduced by the virus. This was a unique method for producing a vaccine that had never been attempted before.

The vitally important next step was the field testing of the vaccine. For a variety of reasons we had decided that we would not be directly involved in the testing of the vaccine. That task was undertaken by Dr. Wolf Szmuness and his colleagues at the New York Blood Bank. Ordinarily, vaccine field trials involve thousands or even hundreds of thousands of individuals; for example, 1.8 million people were involved in the testing of the Salk polio vaccine. Dr. Szmuness’s study required less than a thousand volunteers, but the results were convincing. He showed that the vaccine was highly effective – over 90% protection rate – and it appeared to have no deleterious side effects. He published his report in 1980; within a few years the vaccine was approved by the US Food and Drug Administration primarily based on his HBV vaccine trial. After some hesitation in its use because of the initial high cost, universal national vaccination programs became widespread.

Use of the vaccine was greatly increased after it was produced by the recombinant method by several companies in the US and elsewhere. This was the first widely used vaccine produced by the recombinant method and for many years it was the only one. By the turn of the millennium over a billion doses had been administered and, by May 2003, 151 (79%) of the 192 members countries of WHO had national vaccination programs. It is now one of the most widely used vaccines in the world. The prevalence of HBV carriers and cases has dropped dramatically in the impacted populations. To cite one example of many, in a study in China the prevalence of HBV carriers dropped from the pre-vaccination prevalence of 16.3% to 1.4% after the program had been in place for several years.

The vaccination program has also decreased the incidence of primary cancer of the liver. In a study in Taiwan, the incidence of HCC dropped by two thirds after the program had been in place for only a decade. HBV vaccine is the first “cancer vaccine”, that is, a vaccine that prevents cancer. HBV vaccination is second only to the smoking prevention campaigns as a cancer prevention program. The apparent success of the program has raised expectations that other virally caused cancers caused by cancers may be prevented. The second “cancer vaccine” – against Papilloma virus that causes many cases of cancer of the cervix – has been successfully tested and will probably be widely deployed within a few years. It is likely that many more vaccines to prevent cancer will become available in the future and, I hope, Fox Chase Cancer Center will take a major role in this program.

Plant studiesIn the late 1980s another project began to dominate the research in our laboratory. Would it be possible to devise a therapy for the millions of patients with HBV including many of the approximately 375 million HBV carriers in the world? The concept of rationale design for drug discovery was (and is) in vogue at this time; it is an approach that is based on a molecular understanding of the disease process and the identification of biochemical or biophysical processes of disease at which a medication could be designed to interfere to abort or eliminate the disease. However, most drugs in use have been derived from already existing “natural” chemicals found in plants or other biological material. I decided to look for a medication in the plants that had been used in indigenous medical systems – folk medicine – to see if any of these contained constituents that were anti-viral. My colleagues and I consulted the many texts on folk uses and made a list of all the plants that had been used to treat yellow jaundice, the most obvious symptom of hepatitis. Jaundice can be the result of many diseases, for example, hemoglobinopathies, but probably the most common cause worldwide would be viral, including HBV infection. This resulted in a list of over a thousand plant species. I then sorted the list by the country where the folk medicine was used and identified plant genera that were used on three or more continents or geographic regions. This decreased the number of candidate plants and we finally chose a small weedy plant, Phyllanthus amarus for further study. Phyllanthus species were widely used in India, China, elsewhere in Asia, South and North America, Africa, and in the Pacific for the folk treatment of jaundice. It was also selected because P.S. Venkateswaran, the natural products chemist in our laboratory had known of this plant in his youth. There were also other plants on the short list with which a more limited series of studies were done.

During the next five years or so we collected many of these plants in their native habitat. This resulted in some interesting field trips. I had already engaged in many trips during our research on the distribution of polymorphic traits and in the HBV studies. But this was different. Medical field research is usually done indoors, observing patients in hospitals and populations in villages, towns, and cities. Collecting plants meant that one was outdoors, in the field, forest and jungle; and I enjoyed that very much. There were collecting trips to India (including a fascinating few days in the jungles of the Western Ghats in Karnataka), Nepal (including a long trek in the Himalayas ), England, France, Ireland, Korea, Singapore, Taiwan, and Trinidad and Tobago. There were also extensive collections in the United States ; in California, Colorado, Florida, Hawaii, Louisiana, Maine, Maryland, Massachusetts, New Jersey, New York, Oregon, Pennsylvania, South Carolina, Texas, Vermont, Virginia, and Washington. I usually did these trips when I was traveling for other reasons, to attend meetings or consultations, in order to minimize travel costs.

This research required the establishment of a whole new range of activities in the laboratory. We added a natural products chemist, and a botanist, and developed a series of tests to determine if the medication had any effect on the replication mechanism of HBV. There were no established laboratory animals that could be infected with HBV nor was there then an adequate tissue culture system. However, woodchucks or groundhogs, (Marmota monax) are infected with woodchuck hepatitis virus (WHV) that is very similar to HBV. Hence, we developed skills for trapping and testing woodchucks and raising them in a laboratory setting, a very complicated and difficult operation.

Professor S.P. Thyagarajan at the University of Madras, India had done a controlled clinical trail on the effectiveness of Phyllanthus amarus on the HBV levels in carriers. We helped in the testing of the serum samples from the study and the analysis of the data. This first trial showed an impressive clinical effect. However, subsequent trials in other Asian locations did not confirm the results. We continued in our efforts to isolate the active principles and several other laboratories and commercial companies worldwide have continued research on the preclinical science. Although the plant continues to be used widely in India and elsewhere it has not (at least so far) resulted in a tested and widely used proprietary medication. Research continues and there may be one day another medication to add to the treatment of HBV and other viruses.

India In January of 1986 my wife Jean and I flew to Bangalore, India where, for the next three months, I served as the Raman Professor of the Indian Academy of Sciences at the Indian Institute of Sciences (IISc). We lived in the guest house on the campus of the IISc but I traveled extensively around India giving lectures, consulting with colleagues and collecting information with which to write a report on hepatitis control. India, as many visitors will tell you, is one of the most fascinating places the world. The contrasts were enormous; rural and urban illiteracy and poverty were widespread, but there were large numbers of well educated people and brilliant intellectual communities. I have rarely met such a large number of intelligent academics in one place as at the IISc and several of the other institutions where I was a guest. Bangalore was just beginning to become the center of the information revolution that has spread so rapidly over the world in the past decade.

On 01.20.86 I met with the Prime Minster, Rajiv Ghandi (who was tragically assassinated in 1991) and described my findings for the report that I prepared on the hepatitis problem. I was very impressed with his understanding of the problem and his interest in moving forward with it. In the report I made broad suggestions beyond the issue of vaccine production. I recommended the establishment of graduate level Schools of Public Health. India had several hundred conventional and traditional medical schools at the time but, I believe, only one school of Public health. The use of disposable needles is one of the most important measures to prevent the spread of HBV, HIV, HCV and other blood borne agents. At the time, there were no manufacturing facilities in India for this product and I recommended that they be established. I also commented on an upgrading of water supply in the large cities. Many water systems had been in place for decades without replacement and breaks in the water supply and waste disposal plumbing were common. Since they were sometimes laid near each other, cross contamination, with subsequent disease was common. I also recommended national testing for the prevalence of HBV that could be coupled with surveys for HIV that was then just beginning to spread in India. I also included recommendations on the manufacture of vaccine.

I submitted the report after my return to Philadelphia, and received an acknowledgement of its receipt. Did the report have any effect? It is difficult to know. However, some years later, several schools of public health were established. In 2002 the Hepatitis B Project was initiated in India with the support of the Global Fund for Vaccines and Immunization and, I understand, the vaccination program is accelerating. There are also voluntary programs to encourage vaccination. I became aware of these several years ago when Professor S.P. Singh, Head of the Department of Gastroenterology at SCB Medical College in Cuttack, India wrote to say that July 28, my birthday, would be the date for their annual Hepatitis B Eradication Day in their city. In 2006 it was extended to other parts of India.

Balliol College, Oxford 1989 brought with it a major change in the direction of my scientific career and our family life. I had been a graduate student in Biochemistry at Oxford University in 1955. At Oxford, students become members of one of the colleges; I was attached to Balliol College where my supervisor Alexander Ogston was a Fellow. The years we spent in England still at that time recovering from the economic, social, and psychological damages of World War II, were among the happiest of our married life. The College, possibly the oldest in Oxford, dates to 1263 when John de Balliol, along with his wife Dervorguilla of Galloway, founded the College. Dervorguilla continued his benefactions after his untimely death and gave our College its first code of Statutes, still retained in our archives, that differs remarkably little from the current code. Their son, also named John, was subsequently crowned King of Scotland and there has been a thread of attachment between the College and Scotland from early days.,

I retained a strong affection for Oxford and returned to the University on sabbatical leave in 1972 when I was a Visiting Fellow at Trinity College (of which my biochemistry mentor at Sandy Ogston had become the President), and again in 1983 as the Eastman Professor at Balliol. We had a wonderful time during these years. The Eastman Professorship provided a comfortable home well positioned adjacent to the Balliol cricket pitch and carried very few responsibilities. I gave a series of lectures on scientific process, attended nearly exclusively by members of my family, my squash partners, and fellow rowers. The Balliol graduate accommodation was near our house and we frequently entertained the eclectic bunch of students that made up the international, multi-disciplined, intelligent and very interesting group of young people. I organized the Balliol College Running Group and we hade several happy long distance competitions in the inevitable rain and gloom of an Oxford winter.

But that was not the end of our Oxford experience. In 1988, to my surprise, I was asked if my name could be put forward as a candidate to be the Master of Balliol. I readily agreed and, again to my surprise, was elected. Jean and I came to Balliol in September 17, 1989 to begin my term of office. I was somewhat disappointed that the Porter at the massive gates of the College did not know who I was nor where we were to stay. Despite, or perhaps because of, these initially humbling experiences our five years at Balliol were grand. We entered a world totally different from urban Philadelphia. It included, educational and administrative issues I had not before encountered, interacting with a lively student body and dedicated teaching and research Fellows, formal entertainments at our College and others, and meeting leaders in British and international politics, science, and society. Administering a College in which the Master had no power, but a great deal of influence, were all part of this exciting time.

Did I make much of an impact on the College and its future? It is hard to say. I introduced a “development” program that is an office to solicit funds from alumni, foundations, companies, and others. This form of educational support had not been common in Oxford and Balliol was among the first of the colleges to have a program. I sought to bring the Old Members (alumni) back into the orbit of the College by organizing Master’s Seminars on topics of broad interest to which we invited the Old Members, students, and the Fellows of the College. Balliol has many alumni in the former colonies and current members of the Commonwealth. I traveled extensively (usually in conjunction with scientific meetings and field trips) to meet and speak with them and to take part in seminars away from the College. There were meetings in Toronto, Hong Kong, Singapore, New York, Washington, Tokyo, Paris, and elsewhere.

The college was mainly celebrated for its program in Politics, Philosophy and Economics (“PPE”) that attracted many who subsequently went into government and politics. It had strengths in classics, history, and the humanities. But, we also had a fair share of scientists, particularly at the graduate level. I was, to my knowledge, the first scientist who was Master of Balliol, with the possible exception of an alchemist who served in the 14 th century. I tried to increase the number of students reading science by visiting schools and encouraging science students to apply. But, this was a period in Britain as it was, and is, in the United States, when science was not a popular career choice for young people. We had some success in recruitment and, I like to think, it may have had a long term effect. The social life was demanding. Events, dinners, meetings and parties kept me busy four or five evenings a week and occasionally more. This was a major change from our quite science oriented life in Philadelphia. Our lives were also enriched by our children who, I suppose fortuitously, were in England for long periods during our five years stay. Our oldest daughter Anne was married in the garden of our home, the King’s Mound. My youngest daughter Jane had married Mark Thompson, an Englishman (later, the Director General of the BBC) and they and their growing family would often visit us on weekends. Our second grandchild was delivered in Oxford and Jane stayed with us at the Master’s residence during that time. Another child was born to them during our tenure. If nothing else, that happy event will connect us indelibly with Balliol and Oxford. In the last few years of our stay my oldest son, George, came to Oxford with his family to complete the research for a D. Phil. (Ph.D.) degree. He had been away at school, living in Europe and out of our home for several years. It was a joy to encounter him, each of us on our bicycles, on the narrow streets of central Oxford, and stop for a beer at one of the many pubs that grace the University town. One of his children was also born in Oxford. It was a busy time for reproduction.

I bicycled daily. The automobile traffic in the city was (and is) horrific, but distances are short in central Oxford and I could get anywhere in minutes of earnest peddling. Strangely, among my happiest memories of our stay were the long cycling trips I took into the wonderful Oxfordshire countryside, wrapped in layers of warm clothing, and enclosed in a water resistant outer layer to protect against the frequent rains of the winter (and autumn, spring and summer).

I learned important lessons about management as the Head of an Oxford College. Balliol was originally a collection of clerics who, for a fee, tutored the sons of the wealthy in classics, theology, and a smattering of mathematics, and provided food, lodging, and protection from a sometimes hostile world. To increase their effectiveness, they formed into groups, rented, bought or built, houses in Oxford, and appointed one of their number as the head of the House with different titles (Master, Provost, President, etc.). He (and much later, she) was granted certain stated powers of governance but, over the years, the Fellows (the other clerics), who voted on all issues, took back any absolute powers the Master may have gained. Hence, the Master was accorded honors and privileges, had a great deal of responsibility (if anything went wrong it was the fault of the Master), but no power. Nor did he or she have any staff to speak of. I once asked my predecessor, Sir Anthony Kenny if he could tell me who my staff were. He responded, “What do you mean by Staff?” I replied, “If I tell them to do something, they do it.” He responded, succinctly, but gently, “Your secretary Susan, and your butler, Tony.” So, I had to learn to govern without power, to enlist the voluntary interest of Fellows when there was a specific task to do, guide the College meetings to decrease friction and unneeded controversy, and spend much time doing it. Learning to lead without actual power came in good use in later years when (for example, at the NASA Astrobiology Institute, see below) I had considerable administrative power, but only rarely had need to use it.

Despite these responsibilities there was time for some science. Professor Raymond Dwek asked me to join the Glycobiology Institute, of which he was the Founder and Director; thus began a friendship and collaboration that has lasted since then. We established a program to study the glycosylation of the surface antigen of HBV) a little understood subject. The project quickly turned clinical when Timothy Block, a colleague and friend from Philadelphia came to work on the project during a sabbatical year. We studied the mechanism of the use of partially synthetic sugars to interfere with the glycosylation of the virus in the liver and in vitro. This appeared to hinder the intracellular assembly of the virus in addition to other mechanisms of action. The class of sugar therapies has possible application for the treatment of HBV, HCV, and other viruses that have a glycoprotein surface coating and has resulted in a whole new area of research.

Well, all things, even good things, come to an end and we left Balliol returning home around the world with extended visits in Australia and New Zealand. I served as a Visiting Professor in the Department of Biochemistry at the University of Otago investigating the presence of HBV homologous viral sequences in the human genome. (There are quite a few of them). While on the South Island, Jean and I hiked the Milford Track. It is billed as the most beautiful hike in the world; I agree. I have walked in many parts of Asia, Africa, Europe, and America, and Milford is the most engaging. There were five days of traversing deep glacial valleys, an alpine crossing, huge tree fern forests, and ending in the spectacular Milford Sound. It was a wonderful contrast with the urban life of Oxford and Europe.

The Nasa Astrobiology InstituteAfter returning to Philadelphia I did not re-open my laboratory. In addition to several collaborative research projects I decided to spend some time teaching. In 1997 I was invited to the Program on Human Biology at Stanford University and offered courses in Medical Anthropology and Scientific Process.

Teaching students was pleasant, intellectually stimulating and rewarding because one could ease the access of young people into the life of science. But it was not as exciting as research. While at Stanford I was invited to attend the Astrobiology Roadmap Workshop at the National Aeronautics and Space Administration (NASA) Ames Research Center, at Moffett Field in nearby Mountain View, CA. (07.20.98). I was fascinated by the proceedings. NASA had recently established an astrobiology program and had invited several hundred scientists from the space science and general science communities to discuss and formulate a program for astrobiology. The mission statement for astrobiology is, “The study of the origin, distribution, evolution and future of life on earth and in the Universe”, no mean program. It addressed the heavy questions, “How did life start?” “Are we alone in the universe?” “What is the future of life on earth and elsewhere and what happens to life when it leaves its planet of origin?” Embodied in these questions is the issue of how does one define life, or, if a definition is impossible, what are the characteristics that can be used to identify life. An allied question is what constitutes death and how can you tell if something previously alive is no longer so. These are intriguing questions, of interest not only to scientists but to philosophers, the religious, ethicist, and many others. NASA proposed to study the issues using scientific process. The Workshop encouraged me to learn more about this emerging discipline.

A few months later I was asked to co-chair another roadmap workshop along with the Nobel laureate Richard Roberts; this was on “Genomic Studies on the International Space Station”. It was an exciting program and I met more of the NASA staff during the course of the meeting and its aftermath. Soon afterwards I was asked if I would agree to have my name put forward as the Director of the recently established NASA Astrobiology Institute. This was a surprise since I had not worked in this field before. However, apparently, NASA wanted to have an experienced scientist to take part in the initiation of this scientific program. After interviews with Daniel Goldin, the then Administrator of NASA, I was appointed the “Founding Director” of NAI.

The NAI is a virtual Institute with each of the research teams remaining in their home institutions. They are well funded by NASA and expected to take a part in the NAI activities using direct and electronic means to collaborate. Astrobiology included disciplines in which I did not have formal training; geology, paleontology, oceanography, astronomy, cosmology as well as the engineering that were needed to understand the technology that is a major part of any space mission. The Director had, theoretically, a large measure of control over the grantees’ research, but it was apparent that a top-down hierarchical model for management was inappropriate for the independent minded scientists the field attracted. I relied heavily on the Executive Council, made up of the principal investigators of each of the 11 teams that we funded. Although they were formally an advisory group, I nearly always took their advice, giving them de facto authority. I understood that my mandate was to establish a basic science organization that could discover and understand natural phenomenon that related to early life and to life elsewhere. At an introductory address to the members of the Institute I told them that I did not expect them to do exactly what they said they would do in their applications since, in a fast moving field, observations made after the application had been written could greatly change the path of research. This was greeted with cheers.

Fortunately, NAI attracted outstanding NASA professionals for the NAI staff located at our headquarters at Ames Research Center. This enabled us not only to maintain the efficient operation of the Institute, but also to innovate. There were major barriers to surmount to produce the “Culture of Collaboration” that we sought. These included collaboration between and across scientific disciplines, between different institutions, across geographic distances and different age groups, and between national groups. We developed techniques for realizing our goal of collaboration. These included: a) Modern videoconferencing capability at each of the teams. b) Frequent face to face meetings so that collaborators knew each other personally and could therefore relate better using electronic communication. c) Funding of field trips that included members of several teams. thus increasing the opportunity for people to learn about their colleagues scientific and other interests. d) A website that would bind the participants together and serve as a repository for mutually used data. e) Funding research fellows who could migrate from team to team to facilitate communication between the teams. f) Producing real-time interactive video lectures and conferences that could include members from many teams. The management structure was dispersed rather than command and control; we encouraged the teams to communicate and collaborate directly with each other without the need to go through NASA Central.

NAI has a strong emphasis on international cooperation. Space exploration has been a remarkably international event. Even during the depths of the Cold War Soviet and US astronauts, cosmonauts and space scientists collaborated on projects, as did their governments. We recognized that exploration of the solar system to look for life could not be exclusively a US activity. It is a human program in which nations who wish to collaborate, and can, should be encouraged to do so. Initially, several countries requested and received association or affiliation with NAI in part to demonstrate to their own governments that they had international recognition. Eventually, this was converted to a federal organization of national astrobiology institutes. This has resulted in rich and effective international programs.

The subject matter of astrobiology is fascinating. It includes physical cosmology, an understanding of the origin of elements and chemicals in the early universe; pre-biotic chemistry, that is, how simple organic molecules (many of which are found in space) can assemble to form the long chain molecules – proteins, DNA, RNA, long chain sugars and glycoproteins, fats – that are essential for life as we understand it. Mars and Earth had many similarities in their early days when the environment was much harsher than it currently is. Astrobiology includes the study of locations on contemporary Earth that have similarities to early Earth and, hence, early Mars. The locations include geothermal sites; locations deep under the sea at “black smokers” that form where a tectonic plate subducts under another; in deep ocean sediments and the sub-ocean floor; low and high temperatures; extremes of pH. These are exciting sites for the study of geology and geochemistry and also bacteria, archaea, viruses and multicellular organisms that flourish in what we consider to be harsh environments. I participated in field trips to several of these locations including: Death Valley, an area of high temperature, high salinity and scarce rainfall, Yellowstone National Park, the largest geothermal site in North America, Iron Mountain Mine in northern California whose outflow has a pH approaching zero, the Haughton Impact Crater on Devon Island in the Canadian Arctic Archipelago in the Territory of Nunavut, the salt ponds in Guerraro Negro, Baja California the home to large biomats that are common in contemporary extreme environments and were also common in the cretaceous, Mono Lake below the eastern slope of the Sierras of California where geothermal sites with low pH and high mineral concentrations are found. These made for very interesting trips in the company of a multidisciplinary team of scientists. I formed the NAI Virus Focus Group to study viruses and phage in these environments and we continue to have workshops and field trips.

During the time I directed the NAI I also served (for a year) as Senior Advisor for Biology to the Administrator of NASA at Headquarters in Washington, DC with a focus on Life Sciences. The tag line for the program was “Life beyond its planet of origin” that is, what happens when Earth life is brought into the space environment. In particular, it relates to the health of humans in low earth orbit, on the Moon and eventually on excursions to Mars. Working in Washington, in the shadow of Capitol Hill where the decisions where made on the priorities and funding of NASA was strange, stimulating and frustrating, often at the same time. The Administrator, Daniel Goldin, who I theoretically advised, was a dynamic and visionary leader with a forceful management style. I flew with him on “NASA One” on several occasions to the launches of the Space Shuttle at the Kennedy Space Center. It was a dramatic trip, along with participants in the launch activities in the ageing “G4” (Gulfstream 4 Jet) that was available to NASA. We landed on the rarely used Skid Strip, and, with a police escort proceeded to the Saturn building and then to the viewing platform for the mind-blowing launch. It was a big change from hanging out in a biochemistry laboratory.

I enjoyed my association with NASA over the course of more than five years. I had to learn a whole science that, on most days, found me at the edge of my intellectual capabilities, a happy challenge in my mid-70s. The people I interacted with were different from the medical and biological scientists that had peopled my previous scientific life; aviators, astronauts, astronomers, cosmologists, geologist, oceanographers, paleontologists, senior government and political figures. I enjoyed the outdoors life of California with wonderful walks in the Santa Cruz Mountains, backpack trips into the remote Trinity Mountains near Oregon, miles of walking on lonely beaches with the ocean on one side and shear cliffs on the other. Stanford and the NASA Research Center were in the middle of Silicon Valley and the enthusiasm, entrepreneurial spirit and optimism of the place were a source of stimulation and excitement.

Fox Chase Cancer Center Despite the joys of NASA I was happy to return to Philadelphia and to my activities at the Fox Chase Cancer Center where I had been employed, full or part time since 1964, even during the periods that I was away in Oxford and California. I published several papers on the general biology and ecology of HBV. There are strange interactions of HBV with humans in respect to gender. The response of parents to infection with HBV is related to the gender of their offspring. Parents who become persistent carriers of HBV have a higher ratio of boys to girls among their newborns than do parents who have developed antibody against the surface of the antigen. Uninfected parents have an intermediate ratio. The findings were the same in four populations that we studied and in two populations reported by others. The predicted demographic effect of HBV was very large. In addition, if our observations and inferences were correct, the vaccination program would significantly alter gender ratios in the impacted regions during the next few decades as the program coverage increases.

A measure of validation came from an unusual source. Emily Oster, then a graduate student in Economics in Boston read my book (see above), including the section on gender ratio, and proceeded to examine the issue at a population and economic level. She found a direct correlation between the prevalence of HBV carriers in a population and the ratio of males to females. She also found that in populations with a historic high prevalence of HBV carriers and where effective vaccination had been in place for about two decades, there was, as predicted, a decrease in the male to female gender ratios. If this and our other observations are confirmed it implies that HBV may have a causative role in determining gender ratios at birth.

The American Philosophical SocietyWell, life did not slow down appreciably after I stepped down from NASA employment. In 2005 I was elected the President of the American Philosophical Society. A word about the APS. It was founded in 1743 in Philadelphia by Benjamin Franklin and his colleagues. It is, probably, the oldest academic, scientific, or scholarly society in the United Sates. Its formation followed the publication by Franklin of “A proposal for promoting Useful Knowledge among the British Plantations in America “ that advocated the encouragement of communication between “Men of Speculation, Virtuosi, Ingenious Men”. (Actually, women were included fairly early with the election of the Russian Princess Dashkova in 1789.) The members saw themselves as “Natural Philosophers”; they were active in the scientific revolution that was sweeping Europe at the time; the APS was one of the enlightenment’s North American centers. Among my predecessors as President were the Founder himself and Thomas Jefferson, who was simultaneously the President of the United States. Many of the Founding Fathers of the United States, for example, Washington, John Adams, John Q. Adams, and Alexander Hamilton, as a well as distinguished foreign members – Charles Darwin, Baron Alexander von Humboldt, Joseph Priestley, Antoine Lavoisier, Lord Kelvin (William Thomson) – were Members of the Society. The APS Library contains many important documents from the colonial period and the early days of the Republic including Jefferson’s hand-written draft of the Declaration of Independence, Franklin’s copy of the Constitution, and other icons of the birth of the United States. We also have a growing collection of the papers of contemporary (or recently contemporary) scientists particularly in the area of genetics. They include Thomas Morgan, Ernst Mayr, Theodosius Dobzhansky, Barbara McClintock, Sewell Wright, and many others. It is a major resource for the history of science of the 20th and 21st centuries.

In 2004 to commemorate the 200th anniversary of their epochal expedition, I helped to establish the Lewis and Clark Fund for Exploration and Field Research. The L & C provides funding for field studies by doctoral candidates and others. The amount is small, but sufficient to allow a field trip to most places in the world. We have funded geologists, paleontologists, field biologists, medical epidemiologists, archeologists, anthropologists, etc. It has been wildly popular; we had over 520 applications by the second year of the program. Unfortunately we only have sufficient funds for a fraction of these. It is very gratifying to help young scientists undertake field work that could change the course of their scientific careers.

ConclusionWell, I have written far too much. The award of the Nobel Prize has provided many opportunities that would not have otherwise been available to me. In addition I have had the privilege of meeting many other laureates and their families over the years and attending the grand events held periodically in Stockholm and elsewhere. It has enriched my scientific life and the lives of my wife and family. Our four children have among them now produced nine grandchildren. We spend a great deal of time with them; they are our eyes into the future.

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